Biomimetic Nanomodulator Reprograms Glycolysis-Driven Immunosuppressive Microenvironment to Potentiate Photothermal Immunotherapy in Cold Tumors

Aberrant glycolytic metabolic reprogramming and intrinsic low immunogenicity in “cold” tumors create a hostile immunosuppressive tumor microenvironment (ITME), severely impairing antitumor immunity. Herein, we designed a biomimetic dual-targeting nanomodulator (CM-cRGD@PBG), using mesoporous polydopamine (mPDA) nanoparticles camouflaged with cRGD-modified cancer cell membranes. This multifunctional nanomedicine synchronizes metabolic intervention with cellular immune remodeling to dismantle the ITME. Specifically, the delivered GLUT1 inhibitor BAY-876 reverses lactate-driven immunosuppression by inhibiting M2-like macrophage polarization and regulatory T cell (Treg) expansion. Complementarily, gemcitabine (GEM) is repurposed as a potent immunomodulatory agent to selectively deplete myeloid-derived suppressor cells (MDSCs) and Tregs. Notably, mPDA-mediated photothermal therapy elicits immunogenic cell death (ICD), acting as an in situ nanovaccine that facilitates dendritic cell maturation and antigen presentation. Pancreatic and lung cancer mouse models demonstrate that this “metabolism-chemotherapy-photothermal” strategy exhibits excellent tumor growth inhibition and successfully converts “cold” tumors into “hot” ones, significantly enhancing cytotoxic T lymphocyte (CTL) infiltration and effector function. Our study offers a universal metabolic and immune modulation strategy for “cold” tumors. CM-cRGD@PBG efficiently targets and accumulates at the tumor site via homologous and active targeting. After cellular internalization, the released BAY-876 and GEM remodel the immunosuppressive tumor microenvironment (ITME) by redistributing glucose, inhibiting lactate production, and depleting immunosuppressive cells. Simultaneously, PTT induces apoptosis and triggers ICD to amplify tumor immunogenicity. This strategy reprograms the ITME from an immunosuppressive to an immune-active phenotype, thereby robustly potentiating CTL infiltration and cytotoxicity. • A biomimetic nanomodulator co-loaded with BAY-876 and gemcitabine (CM-cRGD@PBG) was developed. • CM-cRGD@PBG exhibits excellent tumor-targeting ability and photothermal performance. • Enhancing in situ vaccination efficacy of PTT via glycolysis inhibition and immune modulation. • Under laser irradiation, CM-cRGD@PBG inhibits tumor growth via the synergistic “metabolic-chemo-photothermal” strategy. • The strategy reverses immunosuppressive tumor microenvironment and reinvigorates the antitumor immune responses against “cold” tumors.